WO-A-92/01061 describes the preparation of β-lactam derivatives, including ampicillin, via enzymatic acylation of a β-lactam nucleus, for example 6-APA, at high concentrations of acylation agent plus β-lactam derivative. The concentration of the β-lactam nucleus is kept relatively low. From the examples it can be deduced that high conversions are achieved at a high molar ratio of acylation agent to β-lactam nucleus, whereas the conversion is significantly lower at a lower molar ratio of acylation agent to β-lactam nucleus. A disadvantage of the use of a high molar ratio of acylation agent to β-lactam nucleus is that large amounts of acylation agent are lost because of hydrolysis of the acylation agent. In addition it has been found that upgrading of ampicillin is hampered by a relatively large quantity of D-phenylglycine, relative to ampicillin, being present in the reaction mixture obtained after the enzymatic acylation reaction, as a result of which a smaller quantity of ampicillin can be isolated.
It has been found that in order to achieve a high conversion in the process it is of great importance to be able to carry out the reaction at high concentrations, and therefore also at a high concentration of β-lactam nucleus.
WO-A-96/02663 describes a process in which the enzymatic acylation reaction of β-lactam nuclei is carried out at a constant concentration of the reactants. In the continuous process described here the aim is to achieve the highest possible level of concentration of both reactants.
It has been found, however, that when the preparation of ampicillin is carried out at a high concentration of 6-APA, only a relatively low conversion is achieved, compared with conversions which could be achieved in the preparation of other β-lactam derivatives, such as cephalexin.